Enzalutamide resistance is a major obstacle in the treatment of metastatic, castration-resistant prostate cancer (mCRPC). Recently we developed a small-molecule lead compound BKM1644 and demonstrated its potent activity against bone metastatic prostate cancer cells. In this Phase I STTR application, we hypothesize that BKM1644 is a novel targeted therapy to overcome enzalutamide resistance and effectively target bone metastasis. Two Aims are proposed: Aim 1 will evaluate the in vivo pharmacokinetics, distribution and efficacy of BKM1644 in targeting enzalutamide-resistant, bone metastatic prostate cancer in animal models. Aim 2 will determine the mechanism of action of BKM1644 in mCRPC cells. The project has immediate therapeutic potential in treating a lethal disease.